Among patients with BRAFV600-mutated metastatic melanoma, those receiving the BRAF inhibitor dabrafenib had a median PFS of 5.1 months compared with 2.7 months for those given dacarbazine (DTIC-Dome), according to Axel Hauschild, MD, of University Hospital Schleswig-Holstein in Kiel, Germany, and colleagues.

The hazard ratio for disease progression among dabrafenib-treated patients was 0.30 (95% CI 0.18 to 0.51, P<0.0001), the investigators reported online in Lancet.

The results of the study also were recently presented at a meeting of the American Society of Clinical Oncology.

About half of melanomas are associated with one of two mutations in the BRAF gene, "which is constitutively active and drives cell proliferation," the investigators explained.

To confirm the safety and efficacy seen in phase I and II studies of dabrafenib, Hauschild and colleagues enrolled 250 patients from 70 centers, randomizing them to 150 mg of the oral BRAF inhibitor twice daily or intravenous dacarbazine, 1,000 mg/m2, every 21 days.

Patients were in their early 50s, 60% were men, and all were white.

They had unresectable stage III or stage IV disease but good performance status.

As of the cutoff date in December 2011, 57% of patients receiving dabrafenib remained on treatment, as were 22% of those receiving dacarbazine.

In addition, 44% of the dacarbazine patients had crossed over to dabrafenib treatment, which was permitted in the case of disease progression.

A total of 11% of patients receiving the BRAF inhibitor had died, as had 14% of the chemotherapy group, for a survival hazard ratio of 0.61 (95% CI 0.25 to 1.48).

However, the number of deaths thus far has been too small for firm conclusions about overall survival, according to the investigators.

An independent review committee confirmed these objective responses for dabrafenib compared with dacarbazine:

Median time to response was 6.3 weeks in the dabrafenib group and median duration of response was 5.5 months.

The median duration of response has not yet been reached in the dacarbazine group.

The most frequent adverse events in the dabrafenib group were cutaneous effects such as hyperkeratosis and squamous cell carcinomas, as well as arthralgias, fatigue, headache, and fever.

Patients in the dacarbazine group most commonly experienced nausea and vomiting, as well as neutropenia, asthenia, and fatigue.

Most of the adverse effects in both groups were grades 1 or 2.

The investigators pointed out that the "encouraging response rate" should be considered in light of the 5.1 month progression-free survival, "which shows that melanoma cells become resistant quite quickly."

That has also been the case for the other BRAF inhibitor, vemurafenib (Zelboraf), which was approved for use in advanced melanoma in 2011.

This resistance "seems to involve reactivation of the MAPK pathway upstream of MEK," Hauschild and colleagues explained.

Accordingly, a possible strategy for overcoming the resistance mechanisms could involve the use of a MEK inhibitor along with the BRAF inhibitor, they noted.

In a comment accompanying the study, Kim Margolin, MD, of the Seattle Cancer Care Alliance in Washington, predicted that future cancer treatments may involve not only targeted treatments, but also may take aim at the specific mutations underlying resistance mechanisms, "to block driver and resistance pathways simultaneously."

She also observed that "preclinical and clinical data have shown that combining BRAF and MEK inhibition abrogates the risk of low-grade squamous cancers and keratoacanthomas, since their development depends on MEK signaling from upstream activation of RAS in keratinocytes."

Trials are currently in progress evaluating combination BRAF and MEK inhibitors.

The study was sponsored and funded by GlaxoSmithKline.

Many of the investigators reported receiving support and acting as advisers for multiple companies, including GlaxoSmithKline, Roche, Merck, BMS, and Novartis.

Several also are employees of GlaxoSmithKline and hold stock in the company.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner